EP0366277B1 - Formulations pharmaceutiques - Google Patents

Formulations pharmaceutiques Download PDF

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Publication number
EP0366277B1
EP0366277B1 EP89309989A EP89309989A EP0366277B1 EP 0366277 B1 EP0366277 B1 EP 0366277B1 EP 89309989 A EP89309989 A EP 89309989A EP 89309989 A EP89309989 A EP 89309989A EP 0366277 B1 EP0366277 B1 EP 0366277B1
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EP
European Patent Office
Prior art keywords
formulation
biologically active
active material
hydrophobic phase
insulin
Prior art date
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EP89309989A
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German (de)
English (en)
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EP0366277A2 (fr
EP0366277A3 (en
Inventor
Young W. Cho
Michael John Flynn
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Patralan Ltd
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Patralan Ltd
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Priority to AT89309989T priority Critical patent/ATE98480T1/de
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Publication of EP0366277A3 publication Critical patent/EP0366277A3/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1275—Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • hydrophilicity or hydrophobicity (lipophilicity) of the biologically active material is particularly critical
  • the invention readily enables hydrophilic molecules such as insulin, calcitonin (especially salmon calcitonin) and growth hormones or somatotrophin (especially porcine somatotrophin), all of which (particularly salmon calcitonin) are so hydrophilic as to be hygroscopic.
  • microemulsions as the term is used in this specification, is demonstrated by the fact that the microemulsions tend not to separate when left to stand; stability is "sufficient” if it allows for further processing, if desirable or necessary, and/or adequate shelf life. Furthermore, certain microemulsions can be translucent or transparent, often having a coloured tinge.
  • absorbed lower-chained fatty acids are drained into the capillary blood and carried into the hepatic portal vein.
  • Those lipids and fatty acids having relatively longer chains for example oleic acid and di-oleate and tri-oleate glycerides, as well as cholesterol and phospholipids, among other compounds which form chylomicrons within the membrane, are absorbed through the intestinal membrane wall by mechanisms which may not as yet be clearly understood. Once in the intestinal membrane, they participate in the formation of chylomicra and are then 'sucked' into the villae of the intestinal system, drained into the lymph fluid, collected the choracic duct and ultimately dumped into the systemic circulation.
  • hydrophobic-phase miscible organic solvent may be present, again possibly as an aid in formulation.
  • the nature of the solvent will depend on the other materials present. Ethanol is often suitable.
  • the amount of solvent may be, for example from 5 to 50% v/v, based on the volume of the oil phase.
  • each of the surfactants used in the preparation of formulations of this invention be selected from those surfactants classified as anionic or nonionic. These surfactants are particularly useful in pharmaceutical systems for their compatibility, stability, and non-toxicity.
  • Surfactants generally suitable for the various purposes in the present invention include long chain (C16 to C24) fatty acids, e.g. palmitic acid, stearic acid and oleic acid; esters of long chain (C16 to C24) fatty acids, e.g. sodium palmitate, sodium stearate and sodium oleate; sodium lauryl sulphate; polyethylene glycol; polyethylene glycol alkyl ethers; fatty acid esters of polyethylene glycol, e.g.
  • the surfactants of choice will of course be those which are currently on the approved list for pharmaceutical use and will have appropriately low LD50 values. There follows a list of certain exemplary surfactants, together with their HLB values and, where known, their LD50 values.
  • Suitable high HLB surfactants are as follows:
  • the liquid formulation can be coated onto the carrier in a variety of suitable ways, many of which will be well known in the art. Spray coating, for example in a fluidiser bed, is particularly suitable.
  • the carrier will preferably be coated with from 50 to 500% of its weight with the liquid formulation.
  • a solid orally administrable insulin-containing formulation is prepared as follows.
  • Solid core carrier particles are prepared by mixing the following components: Ca carboxymethyl cellulose 200 g Alginic acid 75 g Gelatin 50 g Hydroxypropyl cellulose 175 g Sodium lauryl sulphate 25 g at 22°C.
  • a test sample shows that the particles swell to 200 times their original volume when immersed in water at 38°C.
  • the fluid bed coater/drier is shown, part-sectionally and part schematically in Figure 1, where it is represented generally by reference numeral 1.
  • salmon calcitonin supplied by Rorer; also available from Sigma Chemical Co, St. Louis, Missouri, USA
  • Sufficient salmon calcitonin is added to make 600 to 1200 IU per ml of the final formulation; 1000 IU per ml is the chosen amount.
  • a solid orally administrable salmon calcitonin containing formulation was prepared broadly as described in Example 8, except that 500ml of the liquid formulation of Example 10 was coated onto 400g of carboxymethylcellulose, calcium salt in the modified SPIR-A-FLOW apparatus.
  • Sub-mixture A is prepared from the following ingredients: Soya lecithin 150 g Glyceryl monooleate 22.46g Cholesterol 30 g Ethanol 50 ml by dissolving the first three ingredients in warm (75°C) ethanol and stirring until the other ingredients are dissolved. The ethanol is then evaporated off.
  • a porcine somatotrophin-containing microemulsion is prepared from the following amounts of the sub-mixtures: Sub-mixture B 450 ml Sub-mixture C 150 ml Sub-mixture D 150 ml by adding sub-mixture C slowly to sub-mixture D while stirring with an AUTOHOMOMIXER homogeniser at 7500rpm at 20°C. The resultant mix is slowly added into sub-mixture B using the same mixer at the same temeprature and speed. The resulting emulsion is passed five consecutive times through a microfluidiser, as in Example 1, under the same conditions.
  • Example 8 Using the general procedure of Example 7, but substituting an appropriate amount of human insulin, rather than bovine insulin, a corresponding orally ingestible human insulin formulation is prepared.
  • the liquid formulation may be coated on a solid carrier as described in Example 8.
  • tissue plasminogen activator rather than bovine insulin
  • a corresponding orally ingestible tissue plasminogen activator formulation is prepared.
  • the liquid formulation may be coated on a solid carrier as described in Example 8.
  • Case numbers 1 and 8 are poor responders both to 500mg tablets, per os , of Diabensase and subcutaneously injected 20 units of Regular Insulin, as can be seen as follows:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (61)

  1. Formulation pharmaceutique comprenant une microémulsion ayant une phase hydrophile et une phase hydrophobe, où
    (A) la phase hydrophile est dispersée dans la phase hydrophobe,
    (B) la phase hydrophile contient une matière biologiquement active, et
    (C) la phase hydrophobe contient des chylomicrons ou une matière à partir de laquelle les chylomicrons sont formés in vivo.
  2. Formulation suivant la revendication 1, où la phase hydrophile contient un solvant miscible à l'eau.
  3. Formulation suivant la revendication 1 ou 2, où la phase hydrophobe comprend des chylomicrons précipités de sérum humain, porcin ou bovin avec un polymère vinylique.
  4. Formulation suivant la revendication 1, 2 ou 3, où la phase hydrophobe comprend une matière qui forme les chylomicrons sur la muqueuse intestinale, une telle matière comprend une matière qui forme une matrice de chylomicrons, un phospholipide et un tensioactif lipophile.
  5. Formulation pharmaceutique comprenant une microémulsion ayant une phase hydrophile et une phase hydrophobe, où
    (A) la phase hydrophile est dispersée dans la phase hydrophobe,
    (B) la phase hydrophile contient une matière biologiquement active, et
    (C) la phase hydrophobe contient :
    (i) une matière qui forme une matrice de chylomicrons,
    (ii) un phospholipide, et
    (iii) un tensioactif lipophile.
  6. Formulation suivant la revendication 4 ou 5, où la matière qui forme la matrice de chylomicrons contient du cholestérol.
  7. Formulation suivant la revendication 4, 5 ou 6, où le phospholipide contient de la lécithine.
  8. Formulation suivant l'une quelconque des revendications 4 à 7, où le tensioactif lipophile comprend un acide gras à longue chaîne, estérifié sous forme d'ester de glycérol.
  9. Formulation suivant l'une quelconque des revendications 1 à 8, qui comprend un ester de cholestérol.
  10. Formulation suivant l'une quelconque des revendications 1 à 9, qui comprend une apoprotéine.
  11. Formulation suivant l'une quelconque des revendications 1 à 10, où la phase hydrophobe contient un solvant miscible dans la phase hydrophobe.
  12. Formulation suivant l'une quelconque des revendications 1 à 11, comprenant un tensioactif hydrophile ayant une valeur EHL d'au moins 17.
  13. Formulation suivant la revendication 12, où le tensioactif hydrophile comprend du monostéarate de PEG.
  14. Formulation suivant l'une quelconque des revendications 1 à 13, comprenant un tensioactif lipophile ayant une valeur EHL d'au moins 10.
  15. Formulation suivant la revendication 14, où le tensioactif lipophile comprend du monooléate de glycérol.
  16. Formulation suivant l'une quelconque des revendications 1 à 15, comprenant un ou plusieurs des :
       inhibiteur de protéase;
       stabilisateur de la matière biologiquement active;
       aide à l'émulsion;
       stabilisateur et/ou plastifiant, et/ou conservateur.
  17. Formulation suivant la revendication 5, où la phase hydrophobe comprend : % (v/v) Cholestérol (ou autre matrice) 0,5 - 5 Lécithine (ou autre phospholipide) 0,5 - 10 Tensioactif lipophile 0,5 - 95 Ester de cholestérol 0 - 5 Acide gras non estérifié 0 - 50 Apoprotéine 0 - 4
  18. Formulation suivant l'une quelconque des revendications 1 à 17, où la matière biologiquement active est protéinique.
  19. Formulation suivant la revendication 18, où la matière biologiquement active comprend l'insuline, l'interféron gamma ou l'interféron bêta.
  20. Formulation suivant la revendication 18, où la matière biologiquement active comprend l'insuline.
  21. Formulation suivant l'une quelconque des revendications 1 à 20, où la phase hydrophobe comprend : % (v/v) Cholestérol (ou autre matrice) 0,5 - 5 Lécithine (ou autre phospholipide) 4 - 10 Tensioactif lipophile 50 - 95 Ester de cholestérol 0 - 5 Acide gras non estérifié 0 - 2 Apoprotéine 0 - 4
  22. Formulation suivant la revendication 18, où la matière biologiquement active comprend la calcitonine ou l'érythropoïétine.
  23. Formulation suivant la revendication 18, où la matière biologiquement active comprend la calcitonine de saumon.
  24. Formulation suivant l'une quelconque des revendications 1 à 20, 22 et 23, où la phase hydrophobe comprend : % (v/v) Cholestérol (ou autre matrice) 0,5 - 5 Lécithine (ou autre phospholipide) 0,5 - 7 Tensioactif lipophile 0,5 - 5 Ester de cholestérol 0 - 5 Acide gras non estérifié 0 - 44 Apoprotéine 0 - 4
  25. Formulation suivant la revendication 18, où la matière biologiquement active est une hormone de croissance ou somatotrophine, un activateur de plasminogène tissulaire ou Facteur VIII.
  26. Formulation suivant la revendication 25, où la matière biologiquement active est de la somatotrophine porcine.
  27. Formulation suivant l'une quelconque des revendications 1 à 20, 22, 23, 25 ou 26, où la phase hydrophobe comprend : % (v/v) Cholestérol (ou autre matrice) 0,5 - 5 Lécithine (ou autre phospholipide) 5 - 40 Tensioactif lipophile 10 - 70 Ester de cholestérol 0 - 5 Acide gras non estérifié 0 - 5 Apoprotéine 0 - 5
  28. Formulation suivant l'une quelconque des revendications 1 à 27, qui est sous forme solide et qui comprend un excipient solide enduit de la microémulsion.
  29. Formulation suivant la revendication 28, où l'excipient solide est une matière qui se dilate rapidement au contact d'un liquide aqueux.
  30. Formulation suivant la revendication 29, où l'excipient solide comprend : % (p/p) Carboxyméthylcellulose calcique 20 - 60 Acide alginique 5 - 25 Gélatine 2 - 20 Hydroxypropylcellulose 20 - 60 Tensioactif 0,1 - 20
  31. Formulation suivant la revendication 28, où l'excipient solide a une valeur nutritionnelle.
  32. Formulation suivant la revendication 31, où l'excipient solide est protéinique.
  33. Formulation suivant la revendication 32, où l'excipient protéinique comprend de la poudre de soja.
  34. Formulation suivant l'une quelconque des revendications 1 à 33, qui est formulée pour être protégée de manière entérique.
  35. Formulation suivant la revendication 34, qui est solide et qui est protégée de manière entérique par du phtalate d'hydroxypropylméthylcellulose (HPMC-P).
  36. Formulation suivant l'une quelconque des revendications 1 à 35, qui est sous la forme d'une capsule.
  37. Formulation suivant la revendication 36, où la coque de la capsule contient de la gélatine dure.
  38. Formulation suivant la revendication 37, où la coque de gélatine dure est protégée de manière entérique par du HPMC-P.
  39. Utilisation d'ingrédients d'une formulation suivant l'une quelconque des revendications 1 à 38, dans la préparation d'une formulation administrable par voie orale ou rectale pour le traitement ou la prophylaxie d'un désordre susceptible d'être traité ou contrôlé par une matière biologiquement active.
  40. Utilisation suivant la revendication 39, où la matière biologiquement active est de l'insuline et le désordre est le diabète.
  41. Utilisation suivant la revendication 39, où la matière biologiquement active est de la calcitonine et le désordre est susceptible d'être géré par de la calcitonine.
  42. Utilisation suivant la revendication 39, où la matière biologiquement active est une hormone de croissance et le désordre est susceptible d'être géré par une hormone de croissance.
  43. Procédé d'élevage d'un animal, le procédé comprenant l'administration à l'animal d'une quantité efficace d'une formulation suivant l'une quelconque des revendications 1 à 38, où la formulation est non thérapeutique.
  44. Procédé pour la préparation d'une formulation suivant l'une quelconque des revendications 1 à 38, susceptible d'être ingérée par voie orale ou rectale, le procédé comprenant le mélange des ingrédients.
  45. Procédé suivant la revendication 44, comprenant l'addition d'au moins quelques-uns des composants de la phase hydrophile à au moins quelques-uns des composants de la phase hydrophobe, sous mélange rapide et l'addition des composants restants.
  46. Procédé suivant la revendication 44 ou 45, comprenant :
    (a) un mélange rapide de la matière biologiquement active dans un solvant hydrophile approprié avec la phase hydrophobe, qui contient un tensioactif lipophile, et
    (b) facultativement, l'addition d'un tensioactif hydrophile avec un mélange rapide supplémentaire.
  47. Procédé suivant la revendication 44, 45 ou 46, comprenant l'exposition du mélange résultant à l'action d'un appareil de microfluidisation.
  48. Procédé suivant la revendication 47, ou le mélange est passé trois fois dans un appareil de microfluidisation.
  49. Procédé suivant l'une quelconque des revendications 44 à 48, comprenant le revêtement d'un excipient solide avec la formulation ainsi formée.
  50. Procédé suivant la revendication 49, où l'excipient solide est enduit par vaporisation.
  51. Procédé suivant la revendication 50, où le revêtement par vaporisation est réalisé dans un lit de fluidisation.
  52. Procédé suivant la revendication 51, où le gaz de fluidisation est chauffé quand la température dans le lit de fluidisation est trop faible et où le gaz de fluidisation est refroidi quand la température dans le lit de fluidisation est trop élevée.
  53. Procédé suivant la revendication 51 ou 52, où le revêtement par vaporisation est réalisé à une température de 29°C ± 5°C.
  54. Procédé suivant l'une quelconque des revendications 50 à 53, où le revêtement par vaporisation est intermittent.
  55. Procédé suivant l'une quelconque des revendications 49 à 54, où les particules enduites d'excipient sont granulées.
  56. Procédé suivant l'une quelconque des revendications 49 à 55, où les particules enduites d'excipient sont revêtues de manière entérique.
  57. Procédé suivant l'une quelconque des revendications 44 à 56, où la formulation est encapsulée dans une capsule.
  58. Procédé suivant la revendication 57, où la coque de la capsule contient de la gélatine dure.
  59. Procédé suivant la revendication 58, où la coque de gélatine dure est protégée de manière entérique par du HPMC-P.
  60. Procédé suivant la revendication 59, le procédé comprenant d'abord le revêtement de la capsule avec une matière capable de protéger la gélatine de la capsule des effets nuisibles du chlorure de méthylène et, ensuite, le revêtement de la capsule ainsi protégée par du phtalate d'hydroxypropylméthylcellulose (HPMC-P) au moyen d'une solution de HPMC-P dans du chlorure de méthylène.
  61. Procédé suivant la revendication 60, où la première couche protectrice comprend un mélange de PVP et de HPMC.
EP89309989A 1988-09-29 1989-09-29 Formulations pharmaceutiques Expired - Lifetime EP0366277B1 (fr)

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Also Published As

Publication number Publication date
US5656289A (en) 1997-08-12
EP0366277A2 (fr) 1990-05-02
FI894637A0 (fi) 1989-09-29
BG60849B1 (bg) 1996-05-31
EP0366277A3 (en) 1990-11-28
MX17752A (es) 1993-12-01
CZ554889A3 (cs) 1999-01-13
PT91850A (pt) 1990-03-30
IE63543B1 (en) 1995-05-17
WO1990003164A2 (fr) 1990-04-05
PT91850B (pt) 1996-08-30
NO300199B1 (no) 1997-04-28
BG89877A (bg) 1993-12-24
RO108219B1 (ro) 1994-03-31
RU2122403C1 (ru) 1998-11-27
AU4341789A (en) 1990-04-18
DK481989D0 (da) 1989-09-29
NO893896D0 (no) 1989-09-29
FI98196B (fi) 1997-01-31
DD300405A5 (de) 1992-06-11
ZA897437B (en) 1991-06-26
DE68911473T2 (de) 1994-05-05
JP2927835B2 (ja) 1999-07-28
DK481989A (da) 1990-03-30
CA1339814C (fr) 1998-04-14
AU4243289A (en) 1990-04-05
AU625498B2 (en) 1992-07-16
PL163635B1 (pl) 1994-04-29
ATE98480T1 (de) 1994-01-15
ES2060785T3 (es) 1994-12-01
HU211633A9 (en) 1995-12-28
CZ285237B6 (cs) 1999-06-16
NO893896L (no) 1990-03-30
KR900004327A (ko) 1990-04-12
WO1990003164A3 (fr) 1990-06-14
IE893118L (en) 1990-03-29
FI894637A (fi) 1990-03-30
HUT54033A (en) 1991-01-28
HK85596A (en) 1996-05-24
KR0139641B1 (ko) 1998-06-01
DE68911473D1 (de) 1994-01-27
FI98196C (fi) 1997-05-12
AR243375A1 (es) 1993-08-31
JPH02218609A (ja) 1990-08-31
NZ230838A (en) 1991-03-26
GB8822857D0 (en) 1988-11-02

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